1. Field of the Invention
The invention relates to peptide derivatives and peptidomimetics as inhibitors of transglutaminases, methods for the preparation thereof, pharmaceutical compositions containing said compounds as well as to the use of said transglutaminase inhibitors.
2. Description of the Relevant Art
Transglutaminases are part of the class of transferases and according to EC nomenclature they are correctly designated as “protein-glutamine amine γ-glutamyl transferases” and the EC number EC 2.3.2.13. was assigned to them.
The ε-amino group of the amino acid lysine and the γ-glutamyl group of the amino acid glutamine is linked by them while ammonia is released and an isopeptide bond is formed.
Transglutaminases play an important role in the stabilization of the extracellular matrix (e.g. Aeschlimann and Paulsson, Thromb. Haemostasis, 71, pp. 402-415, 1994) and in programmed cell death (apoptosis) in mammal cells (e.g. Fesus et al., FEBS Lett., 284, pp. 109-11, 1991).
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular field (thrombosis), autoimmune diseases (coeliac disease, Duhring's disease), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (tissue fibrosis) (J. M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279-292).
Coeliac disease, a gluten intolerance, however, is one of the most important indications. Coeliac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In patients concerned, the intestine epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients concerned and is associated with symptoms such as loss of weight, anemia, diarrhea, nausea, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of inhibitors of said enzymes.